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JOURNAL ARTICLE

Generation and characterization of antigen-specific CD4+, CD8+, and CD4+CD8+ T-cell clones from patients with carbamazepine hypersensitivity

Ying Wu, John Farrell, Munir Pirmohamed, B Kevin Park, Dean J Naisbitt
Journal of Allergy and Clinical Immunology 2007, 119 (4): 973-81
17320939

BACKGROUND: Hypersensitivity is a serious manifestation of anticonvulsant therapy characterized by infiltration of the epidermis and dermis by activated CD8(+) and CD4(+) T-cells, respectively. Attempts to characterize drug-specific CD8(+) T cells have been largely unsuccessful.

OBJECTIVES: The aim of these studies was to generate and characterize CD4(+), CD8(+), and CD4(+)CD8(+) T cells in patients with carbamazepine hypersensitivity.

METHODS: Carbamazepine-specific T-cell clones were generated from 5 patients by using modified cloning methodologies. Cell surface receptor phenotype, functionality, and mechanisms of antigen presentation were then compared.

RESULTS: Ninety CD4(+), 23 CD8(+), and 14 CD4(+)CD8(+) carbamazepine-specific T-cell clones were generated. CD4(+) T-cell clones proliferated vigorously with carbamazepine associated with MHC class II but exhibited little cytotoxic activity. In contrast, most CD8(+) T cells proliferated weakly but effectively killed target cells via an MHC class I or MHC class II restricted, perforin-dependent pathway. CD4(+)CD8(+) T cells displayed characteristics similar to those of CD4(+) T cells; however, drug stimulation was demonstrable in the absence of antigen-presenting cells. Carbamazepine was presented to CD4(+), CD8(+), and CD4(+)CD8(+) T cells in the absence of antigen processing. Drug stimulation resulted in the secretion of IFN-gamma and IL-5. A panel of CD11a(+)CD27(-) clones differentially expressed the receptors CXCR4, CCR4, CCR5, CCR8, CCR9, and CCR10.

CONCLUSION: Carbamazepine-specific CD4(+), CD8(+), and CD4(+)CD8(+) T cells exist in the peripheral circulation of hypersensitive patients, often many years after the resolution of clinical manifestations.

CLINICAL IMPLICATIONS: Carbamazepine-specific CD4(+), CD8(+), and CD4(+)CD8(+) T cells displaying different effector functions and homing characteristics persist in hypersensitive patients' blood for many years after resolution of clinical symptoms.

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